Acetaminophen is a commonly used, non-steroidal analgesic agent that is available in over one hundred prescription and over-the-counter formulations. While acetaminophen has fewer gastro-intestinal side effects than aspirin, another commonly used non-steroidal analgesic agent, acute and chronic acetaminophen toxicity can result in gastro-intestinal symptoms, severe liver damage, and even death.
The precise intermediates in the acetaminophen toxic metabolite pathway are not yet known. See, U.S. Pat. No. 4,520,134. It had been thought that when acetaminophen was ingested, the cytochrome P450 dependent enzyme system of the liver produced a potentially toxic metabolite of acetaminophen which was the cause of acetaminophen toxicity. It was further believed that when safe amounts of acetaminophen had been ingested, this toxic metabolite was cleared by hepatic glutathione stores. However in the case of acute or chronic overdose, excessive levels of the toxic metabolite were thought to deplete the glutathione stores in the liver, resulting in hepatic necrosis.
Based on the premise that cytochrome P450 was the agent that mediated the formation of the toxic metabolite, McLean et al., Biochemical Pharmacology 24:37-42, 1975, studied the effect of reducing the amount of cytochrome P450 on acetaminophen-induced hepatic necrosis. They concluded that dietary reduction of cytochrome P450 accompanied by reduction of glutathione did not necessarily diminish acetaminophen toxicity and that the effect of acetaminophen on yeast-fed rats could not be predicted from cytochrome P450 or glutathione levels. However, McLean et al. did find that increases in cytochrome P450 levels did increase acetaminophen toxicity. Therefore, one concludes from these studies that drugs that increase cytochrome P450 levels or concurrently decrease glutathione levels are contraindicated during acetaminophen therapy.
Later studies have proposed that acetaminophen induced hepatic necrosis may be due to cellular oxidative stress, resulting both in lipid peroxidation, protein and nonprotein thiol oxidation, and changes in the intracellular calcium homeostasis. Donatus et al., Biochemical Pharmacology 39:1869-1875, 1990.
Symptoms of acute acetaminophen toxicity are typically mild or non-existent until at least 48 hours post-ingestion. In fact, in children under 12 years of age, acetaminophen toxicity is rarely fatal. Typically, only gastrointestinal irritability is observed in patients within 12-24 hours after ingestion of a large dosage of acetaminophen. Although gastrointestinal symptoms may abate after 24 hours, liver function becomes abnormal. Hepatic failure occurs three to five days after ingestion, and after five days, either the hepatic toxic reaction resolves or death from hepatic failure occurs.
Typically, a dosage of about 140 milligrams per kilogram or more in a child or greater than 10 grams in an adult is toxic. These dosages have been observed to deplete the glutathione reserves of the liver. However, long term dosages as low as three grams per day have resulted in chronic liver disease. When ingestion exceeds 25 grams, mortality is significantly higher. However, the actual amount of acetaminophen that proves toxic depends upon the age, health, weight, sensitivity, and medical condition of the subject. For example, patients suffering from alcoholism, AIDS, or other diseases exhibit greater sensitivity to acetaminophen than do normal patients. The approximate half-life of acetaminophen is about 21/2 hours when it is taken in normal dosages by a normal patient, but the half-life rises to over 4 hours when severe hepatocellular injury has occurred.
Present protocols for the treatment of acetaminophen toxicity include the induction of vomiting, stomach lavage, and/or the immediate administration of acetylcysteine to replenish the hepatic glutathione.
Rosen, U.S. Pat. No. 4,314,989, proposed to reduce the toxic effects of acetaminophen by administering methionine sulphate. The anti-toxin is preferably administered orally within about eight hours of acetaminophen ingestion. See also, U.S. Pat. No. 4,520,134.
Seifter et al., U.S. Pat. No. 4,491,574, reduced adverse side effects and toxicity due to aspirin by the administration of vitamin A and vitamin A precursors, such as beta-carotene, which yield vitamin A or a derivative thereof. Seifter et al. point out that an earlier study had shown that vitamin A could prevent duodenal ulcers and stress ulcers in rats fed 3-, 4-diaminotoluene, which they assert is chemically related to acetylaminophenol.
Nelson, U.S. Pat. No. 4,307,073, administered propylene glycol to alleviate acetaminophen toxicity, while Lamb, U.S. Pat. No. 4,681,897, added a capsaicinoid analgesic compound.
Chem Abstracts 93:108998r discloses the use of beta-carotene to prevent the toxic side effects of antibiotics in plants, and Chem Abstracts 98:74463s discloses the reduction of aflatoxin-induced liver toxicity in chickens by simultaneously administering beta-carotene.
Basu et al., J. Clin. Biochem. Nutr., 3:93-102, 1987, report that fourteen days of dietary beta-carotene supplement reduced cytochrome P450 as measured in mouse liver homogenates, but the authors offer no in vivo data.
Wake, International Review of Cytology, 66:303-353, 1980 describes four cell types found in the liver and the approximate volume occupied by each as hepatocytes (87%), endothelial cells (2.8%), Kupffer cells (2.8%), and stellate cells (1.4%). Bagdon, Toxicology and Applied Pharmacology 2:225-236, 1960, report that beta-carotene is deposited in, and remains sequestered in, only the Kupffer cells of the liver. The present inventors are unaware of any evidence that beta-carotene is stored in any other liver cells. Therefore, the present inventors do not believe that the results of the in vitro study reported by Basu et al. would be relevant in vivo. It is probable that the in vitro homogenization procedure used by Basu et al. would release beta-carotene from the Kupffer cells so that it would come in contact with hepatocytes, or more likely, fragments thereof. This would not occur in vivo. Furthermore, based upon the studies by McLean et al. discussed above, it would appear that a reduction in cytochrome P450 might result in a concurrent reduction in glutathione. This would, in turn, result in increased acetaminophen toxicity as was seen in McLean et al.
Nagasawa et al., U.S. Pat. No. 4,868,114, have found that the biosynthesis of glutathione can be stimulated by administering specific L-cysteine prodrugs.
It has now been discovered that acetaminophen toxicity can be prevented or reduced by the administration of beta-carotene. Furthermore, compositions and unit dosage forms have now been discovered that prevent acetaminophen toxicity and permit the administration to mammals of amounts of acetaminophen that were previously believed to be toxic, thereby increasing the therapeutic effects of the non-steroidal, nonnarcotic analgesic agent, acetaminophen.